JAX Notes April 12, 2011

Gene therapy restores vision in a mouse model of retinitis pigmentosa

Retinitis pigmentosa (RP) is a family of complex inherited eye disease that usually results in partial and sometimes complete blindness. It most often degenerates rod cells but may also degenerate cone cells. As the disease progresses, people lose most of their peripheral vision. Although symptoms may appear in childhood, severe vision loss usually doesn't occur until early adulthood. Retinitis pigmentosa affects about 1 in 4,000 Americans (Medline Plus). One common form of retinitis pigmentosa is caused by autosomal recessive mutations in the beta subunit of rod cGMP-phosphodiesterase (PDE6B) gene, whose encoded protein, PDE6B, controls the levels of cGMP and calcium ions in rod cells. When PDE6B malfunctions, cGMP accumulates in the rods and prevents them from processing light efficiently. Accounting for approximately 5% of all RP cases,PDE6B-RP is one of the earliest onset and most aggressive forms of RP (Pang et al. 2011).

Pde6b-RP mouse models

Pde6b-RP has been studied in two mouse models, the rd1 mouse – C57BL/6J-Pde6brd1-2J/J  – and the rd10 mouse – B6.CXB1-Pde6brd10/J . Each has a different Pde6b mutation. The rd1 mutation degenerates rods extremely rapidly, before much of the retina develops, making the rd1 mouse a difficult model in which to test potential RP therapies. In contrast, the rd10 mutation doesn't begin to degenerate rods until around 18 days of age, after much of the retina is developed, making it a much better model for testing potential retinitis pigmentosa therapies. Additionally, rearing rd10mice in the dark slows the rate of retinal degeneration by as much as four weeks, further enhancing the rd10 mouse's utility for testing potential retinitis pigmentosa therapies.

A successful strategy at last

Initial strategies used to attempt to restore vision in rd10 mice include stem cell, antiapoptotic, antioxidant and gene-replacement therapies. Success has been only partial or temporary. Pang and his colleagues have focused on gene replacement therapies that use increasingly more powerful and efficient vectors. In 2008, they reported that, if applied to 14-day old rd10 mice, a serotype 5, adeno-associated virus (AAV5) Pde6bvector containing a minimal chicken beta actin promoter/CMV enhancer (smCBA) can preserve the functions of rods and cones for at least three weeks (Pang et al. 2008). However, by six weeks, the benefits fade.

Pang and his team hypothesized that the Pde6b transgene expression mediated by the AAV5 vector is too little too late. Other researchers experimented with different vectors. Several demonstrated that a photoreceptor-preferential AAV8 vector is more effective at restoring vision loss in animal models of retinal degeneration (Pawlyk et al. 2005; Sun et al. 2010). In 2009, Pang and his colleagues reported that a fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector mediates earlier and stronger transgene expression in photoreceptor cells than previous AAV8 vectors (Petrs-Silva et al. 2009). In 2011, they reported that injecting this vector sub-retinally in 14-day old rd10 mice rescues rod and cone vision loss for at least six months (Pang et al. 2011).

Dr. Pang and his colleagues are conducting pioneering research in using gene therapy to reverse genetically inherited blindness in animal models. They were the first to successfully use a tyrosine-capsid mutant AAV8 (Y733F) vector to rescue a retinal phenotype and the first to use gene therapy to delay retinitis pigmentosa vision loss for such a long time. Their revolutionary breakthroughs may lead not only to novel therapies for treating Pde6b RP but also to therapies for treating other rapidly progressing retina-degenerating diseases.


Pang, JJ, Boye, SL, Kumar, A, Dinculescu, A, Deng, W, Li, J et al. (2008). AAV-mediated gene therapy for retinal degeneration in the rd10 mouse containing a recessive PDEβ mutation. Invest Ophthalmol Vis Sci 49:4278-83.

Pang JJ, Dai X, Boye SE, Barone I, Boye SL, Mao S, Everhart D, Dinculescu A, Liu L, Umino Y, Lei B, Chang B, Barlow R, Strettoi E, Hauswirth WW. 2011. Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa. Mol Ther 19:234-42.

Pawlyk, BS, Smith, AJ, Buch, PK, Adamian, M, Hong, DH, Sandberg, MA et al. 2005. Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Invest Ophthalmol Vis Sci 46:3039-45.

Petrs-Silva, H, Dinculescu, A, Li, Q, Min, SH, Chiodo, V, Pang, JJ et al. 2009. Highefficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 17:463-71.

Sun, X, Pawlyk, B, Xu, X, Liu, X, Bulgakov, OV, Adamian, M et al. 2010. Gene therapy with a promoter targeting both rods and cones rescues retinal degenerationcaused by AIPL1 mutations. Gene Ther 17:117-31.